Francine K. Welty

Association Between Increased Estrogen Status and Increased Fibrinolytic Potential in the Framingham Offspring Study

BACKGROUND Although extensive evidence indicates that estrogen is responsible for the markedly decreased cardiovascular risk of premenopausal women, the mechanism through which estrogen might exert its protective effect has not been adequately explained. Since thrombosis is now recognized to play an important role in the onset of cardiovascular disease, we investigated the relation between estrogen status and fibrinolytic potential, a determinant of thrombotic risk. METHODS AND RESULTS We determined levels of plasminogen activator inhibitor (PAI-1) antigen and tissue plasminogen activator (TPA) antigen in 1431 subjects from the Framingham Offspring Study. Fibrinolytic potential was compared between subjects with high estrogen status (premenopausal women and postmenopausal women receiving hormone replacement therapy) and low estrogen status (men and postmenopausal women not receiving hormone replacement therapy). In all comparisons, subjects with high estrogen status had greater fibrinolytic potential (lower PAI-1 levels) than subjects with low estrogen status. First, postmenopausal women receiving estrogen replacement therapy had lower levels of PAI-1 than those not receiving therapy (13.0 +/- 0.5 versus 19.5 +/- 1.0 ng/mL, P < .001). Second, premenopausal women had lower levels of PAI-1 than men of a similar age (14.8 +/- 0.6 versus 20.3 +/- 0.8 ng/mL, P < .001); this sex difference diminished when postmenopausal women not receiving hormone replacement therapy were compared with men of a similar age (19.6 +/- 0.7 versus 21.1 +/- 0.7 ng/mL, P = .089). Third, premenopausal women had markedly lower levels of PAI-1 antigen than postmenopausal women not receiving estrogen therapy (14.8 +/- 0.6 versus 19.5 +/- 1.0 ng/mL, P < .001). The between-group differences observed for TPA antigen were similar to those for PAI-1 antigen. CONCLUSIONS Each of these comparisons indicates that the cardioprotective effect of estrogen may be mediated, in part, by an increase in fibrinolytic potential. These findings might provide at least a partial explanation for the protection against cardiovascular disease experienced by premenopausal women, and the loss of that protection following menopause.

Aggressive Versus Moderate Lipid-Lowering Therapy in Hypercholesterolemic Postmenopausal Women Beyond Endorsed Lipid Lowering With EBT Scanning (BELLES)

Background—Women have been underrepresented in statin trials, and few data exist on the effectiveness and safety of statins in this gender. We used sequential electron-beam tomography (EBT) scanning to quantify changes in coronary artery calcium (CAC) as a measure of atherosclerosis burden in patients treated with statins. Methods and Results—In a double-blind, multicenter trial, we randomized 615 hyperlipidemic, postmenopausal women to intensive (atorvastatin 80 mg/d) and moderate (pravastatin 40 mg/d) lipid-lowering therapy. Patients also submitted to 2 EBT scans at a 12-month interval (mean interval 344±55 days) to measure percent change in total and single-artery calcium volume score (CVS) from baseline. Of the 615 randomized women, 475 completed the study. Mean±SD percent LDL reductions were 46.6%±19.9% and 24.5%±18.5 in the intensive and moderate treatment arms, respectively (P<0.0001), and National Cholesterol Education Program Adult Treatment Panel III LDL goal was reached in 85.3% and 58.8% of women, respectively (P<0.0001). The total CVS% change was similar in the 2 treatment groups (median 15.1% and 14.3%, respectively; P=NS), and single-artery CVS% changes and absolute changes were also similar (P=NS). In both arms, there was a trend toward a greater CVS progression in patients with prior cardiovascular disease, diabetes mellitus, and hypertension, whereas hormone replacement therapy had no effect on progression. Conclusions—In postmenopausal women, intensive statin therapy for 1 year caused a greater LDL reduction than moderate therapy but did not result in less progression of coronary calcification. The limitations of this study (too short a follow-up period and the absence of a placebo group) precluded determination of whether progression of CVS was slowed in both arms or neither arm compared with the natural history of the disease.

Effects of Cholesteryl Ester Transfer Protein Inhibition on High-Density Lipoprotein Subspecies, Apolipoprotein A-I Metabolism, and Fecal Sterol Excretion

Objective—Pharmacological inhibition of the cholesteryl ester transfer protein (CETP) in humans increases high-density lipoprotein (HDL) cholesterol (HDL-C) levels; however, its effects on apolipoprotein A-I (apoA-I) containing HDL subspecies, apoA-I turnover, and markers of reverse cholesterol transport are unknown. The present study was designed to address these issues. Methods and Results—Nineteen subjects, 9 of whom were taking 20 mg of atorvastatin for hypercholesterolemia, received placebo for 4 weeks, followed by the CETP inhibitor torcetrapib (120 mg QD) for 4 weeks. In 6 subjects from the nonatorvastatin cohort, the everyday regimen was followed by a 4-week period of torcetrapib (120 mg BID). At the end of each phase, subjects underwent a primed-constant infusion of (5,5,5-2H3)-l-leucine to determine the kinetics of HDL apoA-I. The lipid data in this study have been reported previously. Relative to placebo, 120 mg daily torcetrapib increased the amount of apoA-I in &agr;1-migrating HDL in the atorvastatin (136%; P<0.001) and nonatorvastatin (153%; P<0.01) cohorts, whereas an increase of 382% (P<0.01) was observed in the 120 mg twice daily group. HDL apoA-I pool size increased by 8±15% in the atorvastatin cohort (P=0.16) and by 16±7% (P<0.0001) and 34±8% (P<0.0001) in the nonatorvastatin 120 mg QD and BID cohorts, respectively. These changes were attributable to reductions in HDL apoA-I fractional catabolic rate (FCR), with torcetrapib reducing HDL apoA-I FCR by 7% (P=0.10) in the atorvastatin cohort, by 8% (P<0.001) in the nonatorvastatin 120 mg QD cohort, and by 21% (P<0.01) in the nonatorvastatin 120 mg BID cohort. Torcetrapib did not affect HDL apoA-I production rate. In addition, torcetrapib did not significantly change serum markers of cholesterol or bile acid synthesis or fecal sterol excretion. Conclusions—These data indicate that partial inhibition of CETP via torcetrapib in patients with low HDL-C: (1) normalizes apoA-I levels within &agr;1-migrating HDL, (2) increases plasma concentrations of HDL apoA-I by delaying apoA-I catabolism, and (3) does not significantly influence fecal sterol excretion.

LC-MS-based method for the qualitative and quantitative analysis of complex lipid mixtures

A simple and robust LC-MS-based methodology for the investigation of lipid mixtures is described, and its application to the analysis of human lipoprotein-associated lipids is demonstrated. After an optional initial fractionation on Silica 60, normal-phase HPLC-MS on a YMC PVA-Sil column is used first for class separation, followed by reversed-phase LC-MS or LC-tandem mass spectrometry using an Atlantis dC18 capillary column, and/or nanospray MS, to fully characterize the individual lipids. The methodology is applied here for the analysis of human apolipoprotein B-associated lipids. This approach allows for the determination of even low percentages of lipids of each molecular species and showed clear differences between lipids associated with apolipoprotein B-100-LDL isolated from a normal individual and those associated with a truncated version, apolipoprotein B-67-containing lipoproteins, isolated from a homozygote patient with familial hypobetalipoproteinemia. The methods described should be easily adaptable to most modern MS instrumentation.

Outcomes of Using High- or Low-Dose Atorvastatin in Patients 65 Years of Age or Older with Stable Coronary Heart Disease

Context Data on the benefits of intensive lipid-lowering treatment for elderly persons with heart disease are sparse. Contribution This secondary analysis of a trial examined outcomes of 3809 adults 65 years of age or older with coronary heart disease who were randomly assigned to receive atorvastatin, 80 or 10 mg/d. Patients achieved average low-density lipoprotein cholesterol levels of approximately 1.81 mmol/L (70 mg/dL) and 2.59 mmol/L (100 mg/dL), respectively. Fewer patients who received 80 mg of atorvastatin had major fatal or nonfatal cardiovascular events than did those who received 10 mg of atorvastatin (10.3% vs. 12.6%). Caution The researchers could not determine whether benefits were due to the higher statin dose, lower achieved cholesterol levels, or both factors. The Editors The age profile of the population in most industrialized countries is changing as life expectancy increases. Because cardiovascular risk increases steadily with age, this demographic transition is associated with an increase in the burden of chronic cardiovascular disease (CVD), including coronary heart disease (CHD) and stroke (1). Subgroup analyses from large, randomized, placebo-controlled clinical trials (24) demonstrated that decreasing low-density lipoprotein (LDL) cholesterol levels with statin therapy statistically significantly reduced the risk for CHD in older persons. On the basis of these early trial data, the Third Report of the National Cholesterol Education Program Adult Treatment Panel (5) recommended that persons older than 65 years of age should not be denied the benefits of lipid-lowering therapy. Since publication of the panels report, results of the Heart Protection Study (6) and PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) (7) further support the efficacy and safety of statin treatment in older persons. The outcomes of these 2 studies, along with previous evidence, led the National Cholesterol Education Program to conclude that these data provide a strong justification for intensive LDL cholesterollowering therapy in high-risk older persons with established CVD (8). Recent secondary prevention guidelines from the American Heart Association (AHA) and the American College of Cardiology (ACC) state that it is reasonable to reduce LDL cholesterol levels to less than 1.8 mmol/L (<70 mg/dL) in any patient with established CHD (9). In the ACC and AHA guidelines (10), the writing group acknowledged that elderly patients were underrepresented in many clinical trials and urged physicians and patients to participate in trials that will provide additional evidence for therapeutic strategies in elderly patients. In the TNT (Treating to New Targets) study, intensive lipid-lowering treatment with 80 mg of atorvastatin in patients with stable CHD provided clinically significant benefit beyond treatment with 10 mg of atorvastatin (11). Our prespecified secondary analysis reports data from the TNT study on the efficacy and safety of high-dose atorvastatin treatment in patients 65 years of age or older. Methods Study Design and Patients Details of the TNT study design and outcome measures are published elsewhere (11, 12). After a washout phase, men and women 35 to 75 years of age with established CHD, LDL cholesterol levels between 3.4 and 6.5 mmol/L (130 and 250 mg/dL), and triglyceride levels less than 6.8 mmol/L (<600 mg/dL) were eligible to enter an 8-week, open-label, run-in period with atorvastatin, 10 mg/d. At the end of the run-in phase, 10001 patients with LDL cholesterol levels less than 3.4 mmol/L (<130 mg/dL) were randomly assigned to receive double-blind therapy with atorvastatin, 10 or 80 mg/d. The time of randomization was used as the baseline, and patients were followed for a median of 4.9 years. The primary study outcome was the time to the first occurrence of a major cardiovascular event, defined as death due to CHD, nonfatal nonprocedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke. The prespecified secondary outcomes were a major coronary event, a cerebrovascular event, peripheral arterial disease, hospitalization with a primary diagnosis of congestive heart failure, death from any cause, any cardiovascular event, and any coronary event. An independent end point committee that was blinded to treatment assignment adjudicated all primary and secondary outcomes. Statistical Analysis We tested the statistical significance of treatment effect on end points by using the log-rank test. We calculated hazard ratios with 95% CIs from a Cox regression model that we present where appropriate. We performed homogeneity tests for treatment interaction with age by using a Cox proportional hazards model to determine whether the treatment effects observed in patients 65 years of age or older differed from those in patients younger than 65 years. Role of the Funding Source The TNT study was funded by Pfizer. The steering committee developed the protocol in collaboration with the funding source and was responsible for the final version. ICON Clinical Research, North Wales, Pennsylvania, managed all data. ICON and Pfizer provided site monitoring throughout the study. The data were analyzed by the funding source according to the statistical analysis plan approved by the steering committee. The steering committee had unrestricted, request-based access to the study data, which were retained by the funding source, and developed the article independently without constraints from the sponsor. Results Sample Of 10001 patients randomly assigned in the overall TNT study cohort, 3809 (38%) were 65 years of age or older (1872 received 10 mg of atorvastatin and 1937 received 80 mg). Baseline characteristics and LDL, high-density lipoprotein, and total cholesterol and triglyceride levels were similar between the 2 treatment groups (Table 1). The mean age of the older cohort was 69.9 years. In this group, 2033 patients were 65 to 69 years of age (1000 received 10 mg of atorvastatin and 1033 received 80 mg) and 1776 patients were 70 years of age or older (872 received 10 mg and 904 received 80 mg). The demographic and cardiovascular profiles of patients age 70 years or older were similar to those of the total elderly cohort, including lipid values and previous CVD at baseline. Table 1. Baseline Characteristics of Patients* Lipid Values During the open-label period, LDL cholesterol levels among patients 65 years of age or older decreased from 4.2 mmol/L (163 mg/dL) to 2.5 mmol/L (96 mg/dL). At week 12, mean LDL cholesterol levels were 1.9 mmol/L (72 mg/dL) among those who received 80 mg of atorvastatin and 2.5 mmol/L (97 mg/dL) among those who received 10 mg. Levels of LDL cholesterol in both groups remained stable for the duration of the study. Total cholesterol and triglyceride levels decreased from baseline to week 12 in patients who received 80 mg of atorvastatin and were maintained at this reduced level for the duration of the study. High-density lipoprotein cholesterol levels changed little from baseline levels: At study end, levels had increased by 0.3% for patients who received 10 mg and 0.17% for patients who received 80 mg. Figure 1 shows postrandomization LDL cholesterol and triglyceride levels among patients 65 years of age or older. Figure 1. Mean low-density lipoprotein ( LDL ) cholesterol levels ( top ) and mean triglyceride levels ( bottom ) among patients 65 years of age or older. To convert LDL cholesterol values to mg/dL, divide by 0.02586. To convert triglyceride values to mg/dL, divide by 0.01129. Efficacy Outcomes among Older Patients Among patients 65 years of age or older, a primary event occurred in 199 patients (10.3%) who received 80 mg of atorvastatin and 235 patients (12.6%) who received 10 mg. This is a 2.3% absolute reduction in the rate of major cardiovascular events and a 19% relative reduction in risk in favor of the high-dose group (hazard ratio, 0.81 [95% CI, 0.67 to 0.98]; P= 0.032) (Table 2). After adjustment for well-established risk factors (sex, race, smoking status, history of diabetes, and history of hypertension), the risk reductions associated with 80 mg were similar to the unadjusted results (hazard ratio, 0.81 [CI, 0.67 to 0.98]; P= 0.032). The number needed to treat for benefit for 80 mg versus 10 mg was 35. This value is the number of patients who need to be treated to prevent 1 cardiovascular event over 4.9 years. Table 2. Estimated Hazard Ratios for Individual Components of the Primary Outcome among Patients 65 Years of Age or Older* Table 2 shows the incidence of each component of the primary composite outcome among older patients. Rates of death due to CHD, nonfatal nonprocedure-related myocardial infarction, and fatal and nonfatal stroke (ischemic, embolic, hemorrhagic, or unknown origin) were lower in the 80-mg group than in the 10-mg group. For each individual component, however, the difference was not statistically significant. Eight patients (0.4%) who received 80 mg and 15 patients (0.8%) who received 10 mg had hemorrhagic stroke, which caused 3 deaths in each group. The risk for any cardiovascular event (P< 0.001), a major coronary event (P= 0.128), any coronary event (P< 0.001), a cerebrovascular event (P= 0.010), and hospitalization for congestive heart failure (P= 0.008) was lower in the 80-mg group than in the 10-mg group. The 2 groups did not statistically significantly differ for all-cause mortality and for rates of death due to cardiovascular and noncardiovascular causes. The rate of death due to cardiovascular causes was lower in the 80-mg group than in the 10-mg group (78 patients [4.0%] vs. 83 patients [4.4%]; hazard ratio, 0.91 [CI, 0.67 to 1.24]; P= 0.55). However, more patients in the 80-mg group than the 10-mg group died of noncardiovascular causes (98 patients [5.1%] vs. 76 patients [4.1%]; hazard ratio, 1.26 [CI, 0.93 to 1.70]; P= 0.129). These hazard ratios are consistent with those in the overall

Human Apolipoprotein (Apo) B-48 and ApoB-100 Kinetics With Stable Isotopes

The kinetics of apolipoprotein (apo) B-100 and apoB-48 within triglyceride-rich lipoproteins (TRLs) and of apoB-100 within IDL and LDL were examined with a primed-constant infusion of (5,5,5-(2)H(3)) leucine in the fed state (hourly feeding) in 19 subjects after consumption of an average American diet (36% fat). Lipoproteins were isolated by ultracentrifugation and apolipoproteins by SDS gels, and isotope enrichment was assessed by gas chromatography/mass spectrometry. Kinetic parameters were calculated by multicompartmental modeling of the data with SAAM II. The pool sizes (PS) of TRL apoB-48, VLDL apoB-100, and LDL apoB-100 were 17+/-10, 273+/-167, and 3325+/-1146 mg, respectively. There was a trend toward a faster fractional catabolic rate (FCR) for VLDL apoB-100 than for TRL apoB-48 (6.73+/-3.48 versus 5.02+/-2.07 pools/d, respectively, P=0.06). The mean FCRs for IDL and LDL apoB-100 were 10.07+/-7.28 and 0.27+/-0.08 pools/d, respectively. The mean production rate (PR) of TRL apoB-48 was 6.5% of VLDL apoB-100 (1. 3+/-0.90 versus 20.06+/-6.53 mg. kg(-1). d(-1), P<0.0001). TRL apoB-48 PS was correlated with apoB-48 PR (r=0.780, P<0.0001) but not FCR (r=-0.1810, P=0.458). VLDL apoB-100 PS was correlated with both PR (r=0.713, P=0.0006) and FCR (r=-0.692, P=0.001) of VLDL apoB-100 and by apoB-48 PR (r=0.728, P=0.0004). LDL apoB-100 PS was correlated with FCR (r=-0.549, P=0.015). These data indicate that (1) the FCRs of TRL apoB-48 and VLDL apoB-100 are similar in the fed state, (2) TRL apoB-48 PS is correlated with TRL apoB-48 PR, (3) VLDL apoB-100 PS is correlated with both PR and FCR of VLDL apoB-100 and PR of TRL apoB-48, and (4) LDL apoB-100 PS is correlated with LDL FCR.

Dietary Hydrogenated Fat Increases High-Density Lipoprotein apoA-I Catabolism and Decreases Low-Density Lipoprotein apoB-100 Catabolism in Hypercholesterolemic Women

Objective—To determine mechanisms contributing to decreased high-density lipoprotein cholesterol (HDL-C) and increased low-density lipoprotein cholesterol (LDL-C) concentrations associated with hydrogenated fat intake, kinetic studies of apoA-I, apoB-100, and apoB-48 were conducted using stable isotopes. Methods and Results—Eight postmenopausal hypercholesterolemic women were provided in random order with 3 diets for 5-week periods. Two-thirds of the fat was soybean oil (unsaturated fat), stick margarine (hydrogenated fat), or butter (saturated fat). Total and LDL-C levels were highest after the saturated diet (P< 0.05; saturated versus unsaturated) whereas HDL-C levels were lowest after the hydrogenated diet (P< 0.05; hydrogenated versus saturated). Plasma apoA-I levels and pool size (PS) were lower, whereas apoA-I fractional catabolic rate (FCR) was higher after the hydrogenated relative to the saturated diet (P< 0.05). LDL apoB-100 levels and PS were significantly higher, whereas LDL apoB-100 FCR was lower with the saturated and hydrogenated relative to the unsaturated diet. There was no significant difference among diets in apoA-I or B-100 production rates or apoB-48 kinetic parameters. HDL-C concentrations were negatively associated with apoA-I FCR (r=−0.56, P=0.03) and LDL-C concentrations were negatively correlated with LDL apoB-100 FCR (r=−0.48, P=0.05). Conclusions—The mechanism for the adverse lipoprotein profile observed with hydrogenated fat intake is determined in part by increased apoA-I and decreased LDL apoB-100 catabolism.

Targeting inflammation in metabolic syndrome

The metabolic syndrome (MetS) is comprised of a cluster of closely related risk factors, including visceral adiposity, insulin resistance, hypertension, high triglyceride, and low high-density lipoprotein cholesterol; all of which increase the risk for the development of type 2 diabetes and cardiovascular disease. A chronic state of inflammation appears to be a central mechanism underlying the pathophysiology of insulin resistance and MetS. In this review, we summarize recent research which has provided insight into the mechanisms by which inflammation underlies the pathophysiology of the individual components of MetS including visceral adiposity, hyperglycemia and insulin resistance, dyslipidemia, and hypertension. On the basis of these mechanisms, we summarize therapeutic modalities to target inflammation in the MetS and its individual components. Current therapeutic modalities can modulate the individual components of MetS and have a direct anti-inflammatory effect. Lifestyle modifications including exercise, weight loss, and diets high in fruits, vegetables, fiber, whole grains, and low-fat dairy and low in saturated fat and glucose are recommended as a first line therapy. The Mediterranean and dietary approaches to stop hypertension diets are especially beneficial and have been shown to prevent development of MetS. Moreover, the Mediterranean diet has been associated with reductions in total and cardiovascular mortality. Omega-3 fatty acids and peroxisome proliferator-activated receptor α agonists lower high levels of triglyceride; their role in targeting inflammation is reviewed. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone blockers comprise pharmacologic therapies for hypertension but also target other aspects of MetS including inflammation. Statin drugs target many of the underlying inflammatory pathways involved in MetS.

Sex Differences in the Cardiovascular Consequences of Diabetes Mellitus A Scientific Statement From the American Heart Association

The prevalence of diabetes mellitus (DM) is increasing at a rapid rate. In the United States in 2012, 29.1 million Americans, or 9.3% of the population, had DM.1 Currently, ≈1 in 13 people living in the United States has DM, and 90% to 95% of these individuals have type 2 DM (T2DM).2 Overall, the prevalence of T2DM is similar in women and men. In the United States, ≈12.6 million women (10.8%) and 13 million men (11.8%) ≥20 years of age are currently estimated to have T2DM.2 Among individuals with T2DM, cardiovascular disease (CVD) is the leading cause of morbidity and mortality and accounts for >75% of hospitalizations and >50% of all deaths.3 Although nondiabetic women have fewer cardiovascular events than nondiabetic men of the same age, this advantage appears to be lost in the context of T2DM.4,5 The reasons for this advantage are not entirely clear but are likely multifactorial with contributions from inherent physiological differences, including the impact of the sex hormones, differences in cardiovascular risk factors, and differences between the sexes in the diagnosis and treatment of DM and CVD.6 In addition, there are racial and ethnic factors to consider because women of ethnic minority backgrounds have a higher prevalence of DM than non-Hispanic white (NHW) women. This scientific statement was designed to provide the current state of knowledge about sex differences in the cardiovascular consequences of DM, and it will identify areas that would benefit from further research because much is still unknown about sex differences in DM and CVD. Areas that are discussed include hormonal differences between the sexes and their possible effects on the interaction between DM and CVD, sex differences in epidemiology, ethnic and racial differences and risk factors for CVD in DM across the life …

Effects of the Cholesteryl Ester Transfer Protein Inhibitor Torcetrapib on Apolipoprotein B100 Metabolism in Humans

Objective—Cholesteryl ester transfer protein (CETP) inhibition with torcetrapib not only increases high-density lipoprotein cholesterol levels but also significantly reduces plasma triglyceride, low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (apoB) levels. The goal of the present study was to define the kinetic mechanism(s) by which CETP inhibition reduces levels of apoB-containing lipoproteins. Methods and Results—Nineteen subjects, 9 of whom were pretreated with 20 mg atorvastatin, received placebo for 4 weeks, followed by 120 mg torcetrapib once daily for 4 weeks. Six subjects in the nonatorvastatin group received 120 mg torcetrapib twice daily for an additional 4 weeks. After each phase, subjects underwent a primed-constant infusion of deuterated leucine to endogenously label newly synthesized apoB to determine very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and LDL apoB100 production, and fractional catabolic rates (FCRs). Once-daily 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes by enhancing the FCR of apoB100 within each fraction. On a background of atorvastatin, 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes. The reduction in VLDL apoB100 was associated with an enhanced apoB100 FCR, whereas the decreases in IDL and LDL apoB100 were associated with reduced apoB100 production. Conclusions—These data indicate that when used alone, torcetrapib reduces VLDL, IDL, and LDL apoB100 levels primarily by increasing the rate of apoB100 clearance. In contrast, when added to atorvastatin treatment, torcetrapib reduces apoB100 levels mainly by enhancing VLDL apoB100 clearance and reducing production of IDL and LDL apoB100.